The technical field of this invention is the treatment of neurological diseases and, in particular, the treatment of neurotransmitterdeficiency and dysfunction diseases.
Neurotransmitters are small molecules (less than 1 kilodalton (kD) molecular weight) which act as chemical means of communication between neurons. They are synthesized by the presynaptic neuron and released into the synaptic space where they then effect receptors on postsynaptic neurons.
Neurotransmitter deficits have been implicated in various neurological diseases. Lack of neurotransmitter-mediated synaptic contact causes neuropathological symptoms, and can also lead to the ultimate destruction of the neurons involved. Recently, it has been discovered and disclosed in commonly-owned U.S. patent application Ser. No. 121,626 now a U.S. Pat. No. 4,892,538 that localized delivery of the relevant neurotransmitter to the target tissue may reverse the symptoms without the need for specific synaptic contact.
For example, paralysis agitans, more commonly known as Parkinson's disease, is characterized by a lack of the neurotransmitter, dopamine, within the striatum of the brain, secondary to the destruction of the dopamine secreting cells of the substantia nigra. Affected subjects demonstrate a stooped posture, stiffness and slowness of movement, and rhythmic tremor of limbs, with dementia being often encountered in very advanced stages of the disease.
These clinical symptoms can be improved by the systemic administration of dopamine precursors such as levodopa (L-dopa)(Calne et al. (1969) Lancet ii:973-976), or dopamine agonists such as bromocriptine (Calne et al. (1974) Bri. Med. J. 4:442-444) and (+)-4-propyl-9-hydroxynapthoxacine (de Yebenes et al. (1987) Movement Disorders 2:291-299) both of which are able to cross the blood-brain barrier, and which are converted into dopamine in the brain. Dopamine, itself, cannot be administered systemically because of its inability to cross the blood-brain barrier.
However, a number of drawbacks are incurred when using this type of chemical therapy. For example, other neurological structures which recognize dopamine as a neurotransmitter are also affected. In addition, it becomes difficult to administer the correct drug dosage with time because the "therapeutic window" narrows (i.e., just after administration, the patient is overdosed, exhibiting excessive spontaneous movement; some time thereafter the drug level may become insufficient, causing the patient to again express Parkinsonian symptoms). Furthermore, the limited potency and/or solubility of most available dopamine agonists precludes continuous in vivo infusions as means to reduce motor deficits in Parkinson's disease. Therefore, what is needed is a method of continuous or constitutive delivery of an undegraded, active neurotransmitter to a localized target region deficient in that neurotransmitter.
In an attempt to provide a continuous supply of dopamine and related drugs to the brain at a controlled rate, miniature osmotic pumps have been used. However, limited solubility and stability of dopamine and related drugs, as well as reservoir limitations, have restricted the usefulness of this technology. Controlled sustained release has also been attempted by implanting dopamine encapsulated within bioresorbable microcapsules (McRae-Degueurce et al. (1988) Neurosci. Lett. 92:303-309). However, controlled sustained release of a drug from a bioresorbable polymer relies on bulk surface erosion, for example, due to various hydrolytic events, increasing the likelihood of drug degradation, and rendering predictable release rates difficult.
The implantation of cells capable of constitutively producing the needed neurotransmitter, reportedly in response to environmental needs, has also been attempted. Recently, remedial transplantation of neurotransmitter-secreting tissue has been accomplished using the patient's own tissue so as not to elicit an immune response. For example, dopamine-secreting tissue from the adrenal medulla of patients suffering from Parkinson's disease has been implanted in their striatum with some success. However, this procedure is only used in patients less than 60 years of age, as the adrenal gland of older patients may not contain sufficient dopamine-secreting cells. This restriction limits the usefulness of the procedure as a remedy since the disease most often affects older people.
Furthermore, abdominal surgery performed to excise portions of the adrenal gland poses substantial risks. Moreover, it is not actually known whether it is the dopamine or other "factors" produced by the implanted cells, or the trauma of the surgery, itself, which alleviates the clinical symptoms. In fact, stereotaxic surgery, or the placement of precisely localized lesions in the brain has been practiced in younger, less affected patients without transplantation and this procedure appears to provide similar relief of Parkinsonian symptoms. The procedure is risky, however, and opinions among neurosurgeons still differ as to the best way of making the lesion and what its ideal location should be.
Alternatives to the transplantation of a patient's brain tissue also include the transplantation of either allograft (identical tissue from another of the same species), or xenograft (similar tissue from another of a different species) dopamine-secreting tissue. However, recent studies have shown that although the brain is considered "immuno-privileged", rejection ultimately occurs with both allografts and xenografts. This problem necessitates the co-adminstration of immuno-suppressors, the use of which renders their own set of complications and deleterious side-effects.
Therefore, there exists a need for improved therapies for neurotransmitter-deficiency diseases in general, and in particular, a need for neurological therapy devices which can augment or replace the functions of dysfunctional neurotransmitter-producing areas of the brain without causing excessive trauma. More specifically, there exists a need for a method of providing active, undegraded neurotransmitter to a localized region of the nervous system of a subject deficient in this neurotransmitter, the correct dosage of which will be constitutively delivered over time.
Accordingly, it is an object of the present invention to provide an implantable neurological therapy device useful for the sustained and controlled delivery of a neurotransmitter to a subject, and more particularly, to provide a device which can deliver neurotransmitter to a localized region in the brain of a subject.
It is another object to provide an implantable device that contains and protects neurotransmitter therein from in vivo degradation such that it is delivered to the subject in an active form. Yet another object of the present invention is to provide an implantable device which can deliver an amount of neurotransmitter responsive to in vivo environmental needs. A further object is to provide an implantable, protective cell culture device which is retrievable, and whose contents are renewable with new and/or additional source of neurotransmitter.